One of the major determinants of reinstatement of cocaine use among human addicts is acute re-exposure to the drug, which often precipitates cocaine craving and relapse. This grant proposal will use an animal model of cocaine relapse in order to determine the anatomical and pharmacological determinants of reinstatement of cocaine-seeking behavior following a priming injection. These experiments will focus on the nucleus accumbens and medial prefrontal cortex (mPFC); two nuclei know to play important roles in cocaine reinforcement. All experiments will be performed in rats. Specific Aims 1 and 2 will examine the role of dopamine in the nucleus accumbens and mPFC in cocaine relapse by administering a priming microinjection of cocaine, selective dopamine reuptake blockers, D1-like or D2-like dopamine agonists into the nucleus accumbens or mPFC. In order to assess further the role of specific dopamine receptors in cocaine relapse, selective dopamine receptor antagonists will be administered directly into the nucleus accumbens or mPFC prior to a systemic priming injection of cocaine. Specific Aim 3 will focus on the role of glutamate in reinstatement of cocaine seeking. Although cocaine does not directly influence the glutamate system, recent evidence indicates that ionotropic glutamate receptor agonists administered into the nucleus accumbens reinstate cocaine-seeking behavior. Since the mPFC sends a major glutamatergic projection to the nucleus accumbens, it will be determined if cocaine microinjections into the mPFC reinstate cocaine-seeking behavior by altering glutamate and/or dopamine transmission in the nucleus accumbens. This will be achieved by microinjecting AMPA, NMDA, D1-like or D2-like antagonists into the nucleus accumbens prior to a priming microinjection of cocaine into the mPFC. Collectively, the proposed research will provide fundamental information on the anatomy and pharmacology of relapse to cocaine-seeking behavior and will facilitate the development of effective pharmacological strategies for relapse prevention.